Activity of creatine kinase in a contracting mammalian muscle of uniform fiber type

McFarland, Eric W.; Kushmerick, Martin J.; Moerland, Timothy S.

doi:10.1016/s0006-3495(94)80674-5

Cited by 85 publications

(59 citation statements)

References 52 publications

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“…To some extent, it seems possible to reconcile these datasets and views by recognizing that soleus muscles possess much lower mitochondrial volume densities than hearts. The data obtained by McFarland et al (1994) are therefore consistent with Meyer et al (1984), given what is observable using 31 P-NMR in this system. In hearts with greater mitochondrial volume density, CK net fluxes occurring in opposite directions are observable at the mitochondria and the myofibrils, where compartmentalized or channeled reactions occur, while equal and reversible fluxes are also observed in the cytosol (Joubert et al, 2002).…”

Section: Creatine Kinase and Atp Turnover In Aerobic Musclessupporting

confidence: 81%

“…In their insightful analysis, Meyer et al (1984) argued that the transport functions of creatine and CrP are simply consequences of the near-equilibrium nature of the CK reaction. A decade later, McFarland et al (1994) used a spintransfer NMR method to measure forward and reverse CK flux rates in soleus, a slow-twitch, oxidative muscle. It was found that over a tenfold range of ATP turnover rates, forward and reverse flux rates remain equal and the behaviour of CK in vivo is reconcilable with the kinetic properties of the enzyme in vitro.…”

Section: Creatine Kinase and Atp Turnover In Aerobic Musclesmentioning

confidence: 99%

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Shaken and stirred: muscle structure and metabolism

Suarez

2003

Journal of Experimental Biology

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Muscle fibers, specialized for the conversion of chemical energy into mechanical work, are some of the most highly structured cells known. Muscles perform diverse mechanical functions, ranging from the maintenance of posture and the propulsion of blood, to the movement of limbs for locomotion. They display the largest changes in metabolic rate when undergoing transitions between rest and exercise, as well as the highest metabolic flux rates known in the animal kingdom. From these perspectives, muscles are ideal models for probing the relationships between cell structure and metabolism.In cardiac and locomotory muscles, the transition from rest to exercise is accompanied by an increase in the rate of cellular ATP hydrolysis, brought about by the activation of actomyosin ATPase and, to a variable extent, Ca 2+ -ATPase and Na + -K + -ATPase. Bioenergetic pathways are regulated such that ATP is synthesized at rates that match hydrolysis rates. The stoichiometric matching of rates of synthesis and hydrolysis allows the maintenance of contractile function. Bouts of exercise may vary in both duration and intensity, and many species of animals possess fiber types specialized in structure and biochemical properties to serve their particular needs.Brief (e.g. 1-2·s) bouts of exercise may be accompanied by the Muscles are ideal models with which to examine the relationship between structure and metabolism because they are some of the most highly structured cells, and are capable of the largest and most rapid metabolic transitions as well as the highest metabolic rates known. Studies of metabolism have traditionally been conducted within what can considered as the kinetic paradigm provided by 'solution biochemistry'; i.e. the rates of enzymatic reactions are studied in terms of their regulation by mass-action and allosteric effectors and, most recently, metabolic control analysis of pathways. This approach has served biology well and continues to be useful. Here, we consider the diffusion of small and large molecules in muscles and energy metabolism in the context of intracellular space. We find that in attempting to explain certain phenomena, a purely kinetic paradigm appears insufficient. Instead, phenomena such as the 'shuttling' of high-energy phosphate donors and acceptors and the binding of metabolic enzymes to intracellular structures or to each other are better understood when metabolic rates and their regulation are considered in the context of intracellular compartments, distances, gradients and diffusion. As in all of biology, however, complexity dominates, and to such a degree that one pathway may consist of several reactions that each behave according to different rules. 'Soluble' creatine kinase operates at or near equilibrium, while mitochondrial and myofibrillar creatine kinases directly channel substrate to (or from) the adenine nucleotide translocase and actomyosin-ATPase, their operation being thus displaced from equilibrium. Hexose 6-phosphate metabolism appears to obey the rules of solution biochemistry...

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Section: Creatine Kinase and Atp Turnover In Aerobic Musclessupporting

confidence: 81%

Section: Creatine Kinase and Atp Turnover In Aerobic Musclesmentioning

confidence: 99%

Shaken and stirred: muscle structure and metabolism

Suarez

2003

Journal of Experimental Biology

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“…The complexity of cell structure and the specific behavior of mito-and MM-bound CK has been underestimated in the field of NMR spectroscopy where the cell had mostly been considered as a unique compartment of CK at equilibrium (20,28). As a consequence of this assumption, the free ADP concentration in vivo is estimated from the total concentrations of ATP, PCr, and Cr and the global CK equilibrium constant.…”

Section: Discussionmentioning

confidence: 99%

“…As already pointed out by Wallimann (19), the understanding of CK function might be greatly limited when considering the cell as a homogenous system where enzymes and metabolites have uniform distributions and concentrations. Although the necessity of considering metabolic compartmentation has been previously questioned in NMR analysis of the skeletal muscle (20), its importance was earlier proposed in the heart (21,22) but hardly experimentally explored. Neglecting the presence of mitochondrial compartments in the NMR analysis indeed results in errors on the determination of CK fluxes (23).…”

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confidence: 99%

31P NMR Detection of Subcellular Creatine Kinase Fluxes in the Perfused Rat Heart

Joubert¹,

Mazet

Matéo

et al. 2002

Journal of Biological Chemistry

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The subcellular fluxes of exchange of ATP and phosphocreatine (PCr) between mitochondria, cytosol, and ATPases were assessed by 31 P NMR spectroscopy to investigate the pathways of energy transfer in a steady state beating heart. Using a combined analysis of four protocols of inversion magnetization transfer associated with biochemical data, three different creatine kinase (CK) activities were resolved in the rat heart perfused in isovolumic control conditions: (i) a cytosolic CK functioning at equilibrium (forward, F f ‫؍‬ PCr 3 ATP, and reverse flux, F r ‫؍‬ ATP 3 PCr ‫؍‬ 3.3 mM⅐s ؊1 ), (ii) a CK localized in the vicinity of ATPases (MM-CK bound isoform) favoring ATP synthesis (F f ‫؍‬ 1.7 ؋ F r ), and (iii) a mitochondrial CK displaced toward PCr synthesis (F f ‫؍‬ 0.3 and F r ‫؍‬ 2.6 mM⅐s ؊1 ). This study thus provides the first experimental evidence that the energy is carried from mitochondria to ATPases by PCr (i.e. CK shuttle) in the whole heart. In contrast, a single CK functioning at equilibrium was sufficient to describe the data when ATP synthesis was partly inhibited by cyanide (0.15 mM). In this case, ATP was directly transferred from mitochondria to cytosol suggesting that cardiac activity modified energy transfer pathways. Bioenergetic implications of the localization and activity of enzymes within myocardial cells are discussed.Two major roles have been attributed to the creatine kinase (CK, 1 adenosine triphosphate creatine phosphotransferase, E.C. 2.7.3.2) reaction, which catalyzes the reversible exchange of high energy phosphate:Due to its equilibrium constant favoring ATP synthesis, CK acts as a spatial and temporal buffer for ATP. In addition, due to specific intracellular localization, CK has been suggested to play a key role in energy transfer from sites of ATP production to ATPases by a phosphocreatine (PCr)-creatine (Cr)-CK shuttle. In the myocardial cell, half of the total CK activity is present in the cytosol (cyto-CK), and the other half is accounted for by MM and mitochondrial (mito-CK) isoforms located in the vicinity of other enzymes: a particulate MM-bound CK located in close vicinity to the ATPases of myofibrils, sarcoplasmic reticulum (SR), and sarcolemma (SL) and a mito-CK isoform that is close to the adenine nucleotide translocase (ANT) in the intermembrane space (i.m.s.) of mitochondria. The vicinity of CK with other enzymes was shown to influence enzyme kinetics both in vitro (1, 2) and in skinned fiber preparations (3, 4). Mito-CK is the most obvious example of an exclusive localization in the restricted i.m.s. of the mitochondria where mito-CK octamers and their vicinity to ANT and porin have been proposed to efficiently channel energy from the mitochondria to cytosol (5, 6). The functional consequence of this localization was first evidenced in vitro where the activity of mito-CK changes the apparent affinity of respiration for externally added ADP in isolated mitochondria and saponin-skinned fibers (7-9). In other words there is a restriction of the outer mitochondrial m...

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“…An alternative strategy is to add CK-Mit to a tissue that does not normally contain it, such as the liver, to determine whether there is a gain of function effects. Recently, a transgenic mouse model has been produced that expresses active CK-Mit in liver (22). The CK-Mit localizes properly to the intermembrane space of mitochondria and is capable of synthesizing and utilizing PCr.…”

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confidence: 99%

Transgenic livers expressing mitochondrial and cytosolic CK: mitochondrial CK modulates free ADP levels

Askenasy

Koretsky

2002

American Journal of Physiology-Cell Physiology

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Askenasy, Nadir, and Alan P. Koretsky. Transgenic livers expressing mitochondrial and cytosolic CK: mitochondrial CK modulates free ADP levels. Am J Physiol Cell Physiol 282: C338-C346, 2002. First published October 3, 2001 10.1152/ajpcell.00404.2001.-The function of creatine kinase (CK) and its effect on phosphorus metabolites was studied in livers of transgenic mice expressing human ubiquitous mitochondrial CK (CK-Mit) and rat brain CK (CK-B) isoenzymes and their combination.31 P NMR spectroscopy and saturation transfer were recorded in livers of anesthetized mice to measure high-energy phosphates and hepatic CK activity. CK reaction velocity was related to total enzyme activity irrespective of the isoenzyme expressed, and it increased with increasing concentrations of creatine (Cr). The fluxes mediated by both isoenzymes in both directions (phosphocreatine or ATP synthesis) were equal. Over a 20-fold increase in CK-Mit activity (28-560 mol ⅐ g wet wt Ϫ1 ⅐ min Ϫ1 ), the fraction of phosphorylated Cr increased 1.6-fold. Hepatic free ADP concentrations calculated by assuming equilibrium of the CK-catalyzed reaction in vivo decreased from 84 Ϯ 9 to 38 Ϯ 4 nmol/g wet wt. Calculated free ADP levels in mice expressing high levels of CK-B (920-1,635 mol ⅐ g wet wt Ϫ1 ⅐ min Ϫ1 ) were 52 Ϯ 6 nmol/g wet wt. Mice expressing both isoenzymes had calculated free ADP levels of 36 Ϯ 4 nmol/g wet wt. These findings indicate that CK-Mit catalyzes its reaction equally well in both directions and can lower hepatic apparent free ADP concentrations. mitochondrial creatine kinase; cytosolic creatine kinase; phosphorus-31 nuclear magnetic resonance spectroscopy; magnetization transfer; liver adenosine 5Ј-diphosphate concentration

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Activity of creatine kinase in a contracting mammalian muscle of uniform fiber type

Cited by 85 publications

References 52 publications

Shaken and stirred: muscle structure and metabolism

Shaken and stirred: muscle structure and metabolism

31P NMR Detection of Subcellular Creatine Kinase Fluxes in the Perfused Rat Heart

Transgenic livers expressing mitochondrial and cytosolic CK: mitochondrial CK modulates free ADP levels

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